Highly Pure Crystalline Benzphetamine Hydrochloride and Processes for Preparing

ABSTRACT

A highly pure crystalline form of benzphetamine hydrochloride and methods for the purification and crystallization of benzphetamine hydrochloride in high yield are disclosed.

FIELD OF THE INVENTION

The present invention relates to benzphetamine hydrochloride. Moreparticularly, it relates to highly pure crystalline benzphetaminehydrochloride and processes for preparing crystalline benzphetaminehydrochloride.

BACKGROUND OF THE INVENTION

Benzphetamine hydrochloride, an amphetamine derivative which is ananorectic (also known as “anorexigenic” or appetite suppressant), hasfound use in a variety of applications. The drug was first synthesizedby Heinzelman et al. (U.S. Pat. No. 2,789,138) who found it to be asuperior bronchodilator. Heinzelman et al. disclosed a process for thepreparation of benzphetamine hydrochloride by the benzylation ofd-desoxyephedrine (dextro-methamphetamine) in inert solvent. Thedextro-benzphetamine product was dissolved in ethyl acetate and reactedwith ethanolic hydrogen chloride to yield the benzphetaminehydrochloride salt. As reported by Heinzelman et al., the benzphetaminebase is a colorless, water insoluble liquid. The water solublehydrochloride salt was reported to have a melting temperature of 129° C.to 130° C. Current literature, however, indicates that benzphetaminehydrochloride has a melting point between 152° C. to 153° C. (See theMerck Index, 10^(th) ed.).

Today, benzphetamine hydrochloride is marketed as DIDREX®, a weight lossproduct and anti-obesity preparation, which acts mainly by suppressingthe appetite. The drug has been shown efficacious as part offormulations for decreasing appetite and for the long term management ofobesity. See U.S. Pat. No. 5,543,405 issued to Keown et al., U.S. Pat.No. 5,019,594 issued to Wurtman et al., and U.S. Pat. No. 4,895,845issued to Seed. Benzphetamine hydrochloride has even been used informulations designed to alleviate withdrawal symptoms due to thecessation of tobacco use. See U.S. Pat. Nos. 6,166,032 and 5,900,418,both issued to Viner.

The discovery of a high purity crystalline benzphetamine hydrochlorideprovides an opportunity to improve the performance characteristics of apharmaceutical product.

Further, among the problems associated with the successful commercialdevelopment of formulations incorporating benzphetamine hydrochloride,the synthesis of the compound typically yields an unsolidified oilysubstance of low purity. Accordingly, a post-synthesis method for thepurification and crystallization of benzphetamine hydrochloride isneeded which yields a higher purity product.

SUMMARY OF THE INVENTION

Among the various aspects of the present invention may be noted theprovision of very high purity solid crystals of benzphetamine salt and amethod for the purification and crystallization of benzphetamine salt inhigh yield.

In one aspect of the present invention, the crystalline form ofbenzphetamine hydrochloride has a purity of at least about 95% to about100% by weight. In another aspect, the crystalline form of benzphetaminehydrochloride includes no more than 0.15% of any single impurity.

In yet another aspect of the present invention, the crystalline form ofbenzphetamine hydrochloride has a melting point between about 151° C.and about 158° C.

In still yet another aspect of the present invention, the highly purecrystalline form of benzphetamine hydrochloride is prepared bydissolving benzphetamine hydrochloride in a solvent system including anorganic solvent and an organic modifier to form a solution, heating thesolution to a temperature sufficient to dissolve the benzphetaminehydrochloride in the solvent system, and cooling the solution to atemperature sufficient to precipitate benzphetamine hydrochloride intothe highly pure crystalline form of benzphetamine hydrochloride.

In another aspect of the present invention, the highly pure crystallineform of benzphetamine hydrochloride is prepared by dispersingbenzphetamine hydrochloride in a liquid medium in which benzphetaminehydrochloride is essentially insoluble to form a biphasic mixture,heating the biphasic mixture to a temperature between about 40° C. andabout 95° C., and cooling the biphasic mixture to precipitate the highlypure crystalline form of benzphetamine hydrochloride.

Other objects and aspects of the invention will be, in part, pointed outand, in part, apparent hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a differential scanning calorimetry thermogram ofbenzphetamine hydrochloride.

FIG. 2 is a characteristic powder X-ray diffraction pattern ofbenzphetamine hydrochloride.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT(S)

Benzphetamine hydrochloride is typically present as an oily liquid.Thus, the purification and crystallization processes of the presentinvention advantageously yield high purity solid benzphetaminehydrochloride. The purification and crystallization processes of thepresent invention yield benzphetamine hydrochloride having a purity ofat least about 95% to about 100% in about 60% to about 80% overallyield. Further, the final product contains no more than 0.15% of anysingle impurity and residual solvents are removed such that they arepresent at levels below permitted safety standards. Finally, thecrystalline benzphetamine purified according to the processes of thepresent invention have melting points between about 151° C. and about158° C., more preferably between about 155° C. and about 157° C., whichindicates its high degree of purity.

The highly pure crystalline form of benzphetamine hydrochloride of thepresent invention has been characterized by powder X-ray diffraction(“PXRD”) analysis and thermal methods including differential scanningcalorimetry (“DSC”).

Referring to FIG. 1, the DSC thermogram of benzphetamine hydrochloridedemonstrates the thermal stability of this crystalline form. FIG. 1possesses an endothermic transition (melting/decomposition related) withan onset of approximately 150-155° C. DSC was performed using TAInstruments Q100. A portion of each sample was weighed into a crimpedaluminum sample pan and sealed, and the sample was heated from 25° C. to175° C. at a rate of 5° C./minute. Each sample exhibited a singleendothermic transition as measured by DSC, which is associated withmelting/decomposition of the sample.

The PXRD pattern of benzphetamine hydrochloride is depicted in FIG. 2.Benzphetamine hydrochloride may be characterized by the PXRDcharacteristics set forth in Table 1.

TABLE 1 Scattering Angle (degrees 2θ) d-Spacing ({acute over (Å)}) 8.310.62 9.2 9.62 9.8 9.00 10.8 8.22 11.4 7.73 13.4 6.62 13.9 6.38 14.56.12 15.3 5.77 16.1 5.51 16.6 5.32 17.9 4.94 19.5 4.54 20.0 4.43 20.74.29 21.1 4.22 21.3 4.16 22.2 4.00 22.8 3.90 23.9 3.72 24.9 3.58 25.43.50 25.9 3.44 26.5 3.36 26.8 3.33 27.9 3.20 28.6 3.12 29.3 3.05 29.73.00 30.1 2.96 30.8 2.90 31.1 2.87 31.6 2.83 32.2 2.77 32.9 2.72 33.92.64 35.2 2.55 36.0 2.50 36.3 2.48 37.6 2.39 38.4 2.34 39.4 2.28

The X-Ray diffractometer was Siemens D500 X-ray Diffractometer. Theinstrument utilized a Long Fine Focus X-ray Tube (Type: FL Cu 4KE) and adiffracted beam monochromator mounted in front of a scintillationdetector. Samples were uniformly crushed (not ground) with a spatulaedge, and dispersed on a quartz, zero-background holder. Theexperimental parameters are as follows:

Scan range—2.0 to 40.0 deg 2-theta

Display range—2.0 to 40.0 deg 2-theta

Step size—0.02 deg 2-theta

Scan time per step—1.0 seconds

Radiation source—copper Kα (1.5406 Å)

X-ray tube power—40 kV/30 mA

In one embodiment of the invention, crude benzphetamine hydrochloride ispurified and crystallized by dissolving it into a solvent system,refluxing, and cooling. In this embodiment, the solvent systempreferably comprises an organic solvent and an organic modifier. Crudebenzphetamine hydrochloride is preferably insoluble in the organicsolvent. Preferred organic solvents include ethyl acetate, propylacetate, butyl acetate, toluene, heptane, acetonitrile, acetone,methylene chloride, chloroform, and mixtures thereof, with ethyl acetatecurrently preferred. The preferred organic solvents are miscible withalcohol. The solvent system also comprises an organic modifier whichrenders crude benzphetamine hydrochloride soluble in the solvent system.Preferred organic modifiers are alcohols, and the organic modifier maycomprise methanol, ethanol, isopropanol, n-butanol, n-propanol,isobutanol, and combinations thereof, with n-butanol currentlypreferred. Preferably, the solvent system components and concentrationsare selected such that crude benzphetamine has a solubility of at mostabout 5 g/L to about 15 g/L in the solvent system at room temperature,and at least about 30 g/L to 60 g/L (or more) at the boiling point. Anexemplary solvent system which achieves this solubility is ethyl acetatemodified with n-butanol in which between about 5 mL to 20 mL of ethylacetate is used per gram of crude benzphetamine, preferably betweenabout 10 mL to about 17.5 mL of ethyl acetate is used per grain of crudebenzphetamine hydrochloride, and the solvent system comprises betweenabout 5% to about 10% n-butanol by weight. More preferably, the liquidmedium comprises about 10 mL of ethyl acetate per gram of crudebenzphetamine hydrochloride and about 7.5% n-butanol by weight.

The crude benzphetamine hydrochloride solution is then heated to atleast about 65° C., preferably between about 65° C. to about 85° C.,more preferably between about 75° C. to about 80° C. and refluxed atabout 75° C. to about 80° C., preferably for about 60 minutes. Thesolution can be stirred during heating and reflux.

After reflux, the solution is cooled to between about 5° C. and about15° C., preferably to about 5° C. Cooling from the reflux temperature toambient temperature may proceed by, for example, removing the heatsource, but to reach temperatures between about 5° C. and about 15° C.,the solution may be placed in an ice bath or cooled with a recirculatingchiller. Cooling is preferably controlled such that the cooling rate isslow in order to produce crystals that have a mean particle size ofapproximately 100 to 400 microns. The cooling time from the refluxtemperature to the final temperature is preferably between about 90minutes to about 360 minutes. More preferably, the cooling time isbetween about 120 minutes and about 360 minutes. During cooling, thesolution can be stirred. Once the solution reaches the finaltemperature, the solution is stirred at that temperature for at leastabout 60 minutes to obtain the highest possible yield. Preferably, thesolution is stirred between about 60 minutes and about 120 minutes.

The process of refluxing the solution and slow, controlled coolingcauses the formation of high purity benzphetamine hydrochloride crystalsin high yield. The crystals may be isolated by filtering and washingwith cold solvent in which the crystals are insoluble, preferably icecold ethyl acetate, or by centrifugation. Refluxing and coolingaccording to the above described process in an ethyl acetate/n-butanolliquid medium, for example, results in crystallized benzphetamine inpurity from about 95% to about 100% in about 60 to about 80% yield fromthe starting material. The final product contains no more than 0.15% ofany single impurity and residual solvents are removed such that they arepresent at levels below permitted safety standards.

Advantageously, the purification and crystallization processes describedabove yield a higher purity, drier crystal product which may be reliablyrecrystallized to yield a very high purity recrystallized product withhigher yield than known processes which do not utilize the purificationand crystallization processes of the present invention.

Recrystallization involves re-dissolving the purified and crystallizedbenzphetamine hydrochloride in a suitable solvent system and slowlygrowing very high purity crystals by a variety of methods. Suitablesolvent systems comprise at least one organic or inorganic solvent inwhich benzphetamine hydrochloride is soluble. Desirable solubility is atleast 25 grams per liter at elevated temperature (boiling) and no morethan about 5 grams per liter at cold (0 Celsius) temperatures. In somerecrystallization processes, the solvent system may comprise inorganicsolvent(s). Preferably, however, the solvent system comprises organicsolvent(s) which are protic and volatile. In one embodiment, the organicsolvents have a low boiling point (below 100° C.) to facilitate drying,low toxicity, a high degree of selectivity between benzphetaminehydrochloride and its impurities, and an absence of an azeotrope if amixture of more than one solvent is used (in order to facilitaterecovering or recycling the solvents.) Accordingly, suitable organicsolvents include ethyl acetate, methanol, ethanol, isopropanol,N-butanol, acetone, acetonitrile, methylene chloride, and chloroform.Preferred organic solvents include ethyl acetate, acetone, andacetonitrile. In some recrystallization processes, the solvent systemcomprises two or more organic solvents. Preferable solvent systems withtwo or more organic solvents include N-butanol/ethyl acetate andmethanol/ethyl acetate.

Recrystallization preferably occurs by slow growth of benzphetaminehydrochloride crystals from the organic solvent. This can be achieved,for example, by vapor diffusion or slow evaporation. Vapor diffusioninvolves the dissolution of benzphetamine crystals in a suitable liquidsolvent and placing the liquid solvent in an atmosphere comprising avapor. Preferably, the liquid solvent is an organic solvent such asisopropanol. Preferably, the atmosphere comprises a volatile organicmolecule, such as ethyl acetate. In an exemplary isopropanol/ethylacetate vapor diffusion system, about 185 mg of benzphetaminehydrochloride can be dissolved in approximately 2 mL of isopropanol in asmall vial. The small vial can be placed into a 50 mL vessel, which cancontain about 5 to about 6 mL of ethyl acetate. The vessel is thensealed.

Alternatively, recrystallization may occur by slow evaporation. Slowevaporation involves the dissolution of benzphetamine crystals in asuitable liquid solvent and allowing the liquid solvent to evaporateover the course of an extended period of time. Suitable solvents forcrystal growth by slow evaporation include acetonitrile, water, acetone,methanol, ethanol, isopropanol, n-butanol, ethyl acetate, methylenechloride, and chloroform. Currently preferred solvents includeacetonitrile and acetone. In some recrystallizations, the liquid solventmay comprise two or more solvents. An exemplary two-solvent system isethyl acetate/methanol. Suitable solvents are capable of dissolvingbenzphetamine and are preferably volatile. Highly volatile solvents arenot preferred however because rapid evaporation may result in amorphousmaterial. Preferably, the benzphetamine crystals to be recrystallizedare dissolved in the liquid solvent to saturated or near-saturatedconcentrations. For example, where acetonitrile is the solvent, betweenabout 5 mg and about 10 mg benzphetamine is dissolved per 1 mL ofacetonitrile solvent to reach near saturated solution. For acetone,between about 5 mg and about 10 mg benzphetamine is dissolved per 1 mLof acetone solvent to reach near saturation. For the two-solvent ethylacetate/methanol system, between about 5 mg and about 10 mgbenzphetamine is dissolved per 1 mL of liquid solvent to reach nearsaturation. The slow evaporation of the liquid solvent yields asupersaturated solution from which crystals consistent withbenzphetamine hydrochloride of FIGS. 1 and 2 may form and grow with veryhigh purity and high yield.

The high purity benzphetamine hydrochloride crystals of the presentinvention have sufficient purity for their intended pharmaceuticalpurpose. As such, benzphetamine crystals which were purified accordingto the processes of the present invention may be incorporated intopharmaceutical preparations.

EXAMPLES

The following examples further illustrate the present invention.

Example 1

For crystallization, ethyl acetate (49 mL) was added to benzphetaminehydrochloride oil (27.38 g), and the mixture was refluxed. The oil wouldnot completely dissolve. After removal from heat, white crystals formed.The resin and crystals from ethyl acetate reflux were recrystallizedusing ethyl acetate (102.1 g) and isopropanol (17.29 g). Additionalethyl acetate (131.7 g) failed to yield crystals. So, the solution wasstirred and cooled and crystals (4.59 g, first crop) formed afterseveral minutes. The crystals were filtered and washed with ethylacetate (50 mL) and dried in a vacuum oven. Overnight, an additionalcrop of crystals (8.09 g, second crop) formed in the filtrate. A sampleof this second crop was taken for analysis.

The first crop of crystals had a melting point range from 153.9 to155.5° C. Analysis showed that these crystals were 96.3% benzphetaminehydrochloride The second crop of crystals was dried in oven at 62° C.leaving 7.83 g of off-white solid having a melting point range between154 and 156.3° C.

Example 2

Crude benzphetamine hydrochloride (three samples of 2.00 grams each forcrystallization from ethyl acetate/methanol, ethyl acetate/ethanol, andethyl acetate/isopropanol and 0.93 grams for crystallization from ethylacetate/n-butanol) was added to ethyl acetate (50 mL each forcrystallization from ethyl acetate/methanol, ethyl acetate/ethanol, andethyl acetate/isopropanol and 25 mL for crystallization from ethylacetate/n-butanol) and heated to a very gentle boil in a water bath.Into each mixture was added enough organic modifier to dissolve thesolids. In this experiment, the organic modifiers used were isopropanol,methanol, ethanol, and n-butanol. The four batches were removed fromheat and allowed to cool to ambient temperature, and then cooled in anice bath at 5° C. for 30 minutes. The slurries were filtered in a 4.25cm Buchner funnel with Whatman No. 40 filter paper. The filter cakeswere washed with ice cold ethyl acetate (7 mL). The samples were testedby HPLC, and the results are shown in Table 2.

TABLE 2 Alc. Vol. Yield Benzphetamine Experiment (mL) (g) Area % CrudeN/A N/A 87.17 Isopropanol#1 2.5 1.16 97.50 Isopropanol#2 0.02 3.52Isopropanol#3 0.02 3.87 Ethanol 1.5 1.42 94.34 Methanol 1.00 1.36 95.03n-Butanol 0.75 0.57 97.12

It was observed that the ethyl acetate/isopropanol filtrate continued toproduce solids. Isopropanol #2 represents the content of the solidsisolated one day after the initial experiment, and Isopropanol #3represents the content of the solids isolated two days later. Thesesamples contained almost all impurity.

The product of the n-butanol crystallization was purer than the productscrystallized from methanol or ethanol. The yield from n-butanolcrystallization was 61.3% (0.57 grams product from 0.93 grams crude).This exceeded the yield from isopropanol (58%) but was less than theyield from ethanol (71%) and methanol (68%.) The concentration ofbenzphetamine in the filtrate was 7.8 mg/mL, 6.07 mg/mL, 6.67 mg/mL, and4.29 mg/mL for isopropanol, ethanol, methanol, and n-butanolcrystallizations, respectively.

The above experiments were repeated (except for ethanol) and the resultsare summarized below in Table 3.

TABLE 3 Alc. Vol. Yield Benzphetamine Experiment (mL) (g) Area % CrudeN/A N/A 96.36 isopropanol 2.5  1.56 99.08 methanol 0.75 1.61 99.25n-butanol 2.25 1.53 99.42

The benzphetamine crystallized in ethyl acetate/n-butanol was purer thanthe material crystallized from other alcohols. In addition,particle-size characterization by Scanning Electron Microscopy (SEM)showed that the product crystallized using n-butanol had a betterdefined rod-like crystal morphology than product made with the otheralcohols (although methanol gave very similar crystals) and toluene(plate-like crystal morphology). Without being bound by theory, it isthought that the rod-like crystal form produces a more uniform blendduring formulation than plate-like crystals.

Example 3

The following experiments were run according to the process set forth inExample 2:

TABLE 4 Run Order/ EtOAc Usage N - butyl alcohol Cooling TimeNotebook/Page (ml/g) Concentration (wt. %) (minutes) 1 discard 10 15 1502 25 10 90 3 25 5 90 4 17.5 7.5 120 5 25 5 150 6 10 5 90 7 10 10 90 8 105 150 9 25 10 150 1 rerun 10 10 150

Results of the experiments are presented in Table 5. This table presentsthe percent yield of crystallized benzphetamine HCl and the area percentpurity.

TABLE 5 Experiment Yield (%) Area % Crude 97.04 1 72.98 98.92 2 0.00 N/A3 74.09 98.82 4 67.87 98.87 5 71.50 98.81 6 91.19 98.65 7 71.99 98.89 889.12 98.71 9 3.37 99.10

These results indicate that the yield was sensitive to the ethyl acetateusage and concentration of n-butanol. The yield improved as both werereduced. The cooling rate had no effect upon yield and a negligibleeffect upon purity.

The time the batch was stirred after reaching the final temperature wasalso investigated and found that a slight loss in yield results if thebatch was stirred for less than 1 hour at the final temperature.

Further, particle size analysis was performed on these experimentsamples by laser diffraction. It was found that finer particle sizes instirred samples may be caused by using a low (5%) concentration ofalcohol, and that coarse particle sizes in sonicated samples may becaused by a high (10%) concentration of alcohol. Without being bound toa particular theory it is thought that low concentrations of alcoholleads to less agglomeration of individual benzphetamine hydrochloridecrystals, and that a high concentration leads to strong agglomerationsor aggregations that do not disperse when exposed to ultrasound.

Example 4

Crystallized benzphetamine hydrochloride was subjected to vapordiffusion recrystallization and analyzed by PXRD analysis. Benzphetaminehydrochloride (184.79 mg) was dissolved in isopropanol (2 mL) in a 10 mLvial. The vial was placed in a jar containing ethyl acetate (5 to 6 mL)and sealed. The slow vapor diffusion of ethyl acetate into the vial overa period of weeks produced crystals consistent with the PXRD pattern ofbenzphetamine hydrochloride of FIG. 2.

Example 5

Crystallized benzphetamine hydrochloride was subjected to slowevaporation recrystallization from several solvents and analyzed by PXRDanalysis.

Benzphetamine hydrochloride was added to saturated/near saturatedsolvent systems (1 mL each of acetonitrile, water, acetone, methanol,ethanol, isopropanol, n-butanol, ethyl acetate/methanol, methylenechloride, and chloroform). The resulting solutions were placed in smallvials and set aside at room temperature in a nitrogen purged desiccatorto allow for crystal growth.

Crystals obtained by slow evaporation were uniformly crushed with aspatula edge and dispersed on quartz zero-background holders. Thepowders were subjected to PXRD analysis. The results are summarized inTable 6.

TABLE 6 Solvent Powder Morphology Acetonitrile Crystals Acetone CrystalsEthyl acetate/methanol Crystals

The powder patterns obtained from acetonitrile, acetone, and ethylacetate/methanol grown crystals were consistent with the presence ofbenzphetamine hydrochloride of FIG. 2.

In view of the above, it will be seen that the several objects of theinvention are achieved and other advantageous results attained.

When introducing elements of the present invention or the preferredembodiment(s) thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising”, “including” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

All patents, applications, and other references cited herein areincorporated herein by reference in their entirety.

As various changes could be made in the above without departing from thescope of the invention, it is intended that all matter contained in theabove description and shown in the accompanying drawings shall beinterpreted as illustrative and not in a limiting sense.

1. A highly pure crystalline form of benzphetamine hydrochloride.
 2. Thecrystalline form of benzphetamine hydrochloride of claim 1 having apurity of at least about 95% to about 100% by weight.
 3. The crystallineform of benzphetamine hydrochloride of claim 1 having no more than 0.15%of any single impurity.
 4. The crystalline form of benzphetaminehydrochloride of claim 1 having a melting point between about 151° C.and about 158° C.
 5. The crystalline form of benzphetamine hydrochlorideof claim 1 having a melting point between about 155° C. and about 157°C.
 6. The crystalline form of benzphetamine hydrochloride of claim 1having rod-like crystal morphology.
 7. The crystalline form ofbenzphetamine hydrochloride of claim 1 having plate-like crystalmorphology.
 8. A process for preparing a highly pure crystalline form ofbenzphetamine hydrochloride comprising: a) dissolving benzphetaminehydrochloride in a solvent system comprising an organic solvent and anorganic modifier to form a solution comprising benzphetaminehydrochloride, the organic solvent, and the organic modifier; b) heatingthe solution to a temperature sufficient to dissolve the benzphetaminehydrochloride in the solvent system; and c) cooling the solution to atemperature sufficient to precipitate benzphetamine hydrochloride intothe highly pure crystalline form of benzphetamine hydrochloride.
 9. Theprocess of claim 8 wherein the organic solvent is miscible with alcohol.10. The process of claim 8 wherein the organic solvent is selected fromthe group consisting of isopropanol, ethanol, methanol, ethyl acetate,propyl acetate, butyl acetate, toluene, heptane, acetonitrile, acetone,methylene chloride, chloroform, and mixtures thereof.
 11. The process ofclaim 8 wherein the organic solvent is ethyl acetate.
 12. The process ofclaim 11 wherein between about 5 mL to about 20 mL of ethyl acetate isused per gram of benzphetamine hydrochloride.
 13. The process of claim11 wherein between about 10 mL to about 17.5 mL of ethyl acetate is usedper gram of benzphetamine hydrochloride.
 14. The process of claim 11wherein the organic modifier is selected from the group consisting ofmethanol, ethanol, isopropanol, n-butanol, n-propanol, isobutanol,t-butyl alcohol and combinations thereof.
 15. The process of claim 8wherein the modifier is n-butanol.
 16. The process of claim 15 whereinthe solvent system comprises n-butanol in a concentration between about5% and about 10%.
 17. The process of claim 15 wherein the solvent systemcomprises n-butanol in a concentration of about 7.5%.
 18. The process ofclaim 11 wherein heating the solution comprises heating to a temperatureof at least about 65° C.
 19. The process of claim 11 wherein heating thesolution further comprises the step of refluxing the solution at atemperature between about 65° C. and about 85° C. between about 15minutes and about 60 minutes.
 20. The process of claim 11 whereincooling the solution comprises cooling to a temperature between about 5°C. and about 15° C. occurs over a cooling time between about 90 minutesto about 360 minutes.
 21. The process of claim 11 wherein cooling thesolution comprises dissolving the benzphetamine hydrochloride at atemperature between about 5° C. and about 15° C. for at least about 60minutes.
 22. The process of claim 11 further comprising the step ofisolating the crystalline form of benzphetamine hydrochloride byfiltration, distillation, and centrifugation.
 23. The process of claim11 further comprising the step of recrystallizing the crystalline formof benzphetamine hydrochloride by vapor diffusion or slow evaporation.24. The process of claim 23, wherein the slow evaporation is conductedin solvent systems selected from the group consisting of acetonitrile,acetone, and ethyl acetate/methanol.
 25. A process for preparing ahighly pure crystalline form of benzphetamine hydrochloride comprising:a) dispersing benzphetamine hydrochloride in a liquid medium in whichbenzphetamine hydrochloride is essentially insoluble to form a biphasicmixture comprising benzphetamine hydrochloride and the liquid medium; b)heating the biphasic mixture to a temperature between about 40° C. andabout 95° C.; and c) cooling the biphasic mixture to precipitate thehighly pure crystalline form of benzphetamine hydrochloride.
 26. Theprocess of claim 25 wherein the liquid medium is selected from the groupconsisting of toluene, ethyl acetate, and xylenes.
 27. The process ofclaim 25 wherein the biphasic mixture is heated to a temperature betweenabout 40° C. and about 95° C.
 28. The process of claim 25 furthercomprising the step of agitating the biphasic mixture.
 29. The processof claim 28 wherein agitating the mixture comprises stirring the mixtureat about 500 to about 1200 rpm.
 30. The process of claim 28 whereinagitating the mixture comprises stirring the mixture at about 120 rpmwith a stirrer having a paddle with a 2.5 ft radius.
 31. The process ofclaim 25 further comprising the step of isolating the highly purecrystalline form of benzphetamine hydrochloride by filtration orcentrifugation.
 32. The process of claim 25 further comprising the stepof recrystallizing the purified solid form of the crystalline form ofbenzphetamine hydrochloride.